Cc1 cancer derma

Cancer Cancer ChemotherapyChemotherapy

Prof. Ghada HashemProf. Ghada Hashem

Faculty of Medicine – Cairo Faculty of Medicine – Cairo University University

50.2 Rang

EtiolopathologyEtiolopathology

ApoptosisApoptosis Programmed cell Programmed cell

deathdeath Cascade of Cascade of proteases proteases

initiate processinitiate process

Major approaches to therapy of Major approaches to therapy of cancers cancers

Cell Cycle = Cell Cycle = Growth, DivisionGrowth, Division

Cell Cycle Specific (CCS) & Cell Cycle Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)Non-Specific Agents (CCNS)

General problems with General problems with anticancer drugsanticancer drugs

Most of them are antiproliferative, i.e. Most of them are antiproliferative, i.e. they damage DNA and so initiate they damage DNA and so initiate apoptosis.apoptosis.

They also affect rapidly dividing They also affect rapidly dividing normal normal cells.cells.

This leads to toxicity which are usually This leads to toxicity which are usually severe.severe.

To greater or lesser extent the To greater or lesser extent the following toxicities are exhibits by all following toxicities are exhibits by all anticancer drugs.anticancer drugs.

Chemotherapeutic agents are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction.

Proliferating cellsProliferating cells are are especially sensitive to especially sensitive to chemotherapy chemotherapy because because cytotoxic cytotoxic drugsdrugs usually act by usually act by disrupting DNA disrupting DNA synthesis or mitosissynthesis or mitosis, , cellular activities that cellular activities that only proliferating cells only proliferating cells carry out.carry out.

Unfortunately, toxicity Unfortunately, toxicity

to the anticancer to the anticancer agents is to any agents is to any rapidly dividing cells. rapidly dividing cells. (e.g. (e.g. bone marrow, bone marrow, hair follicles, sperm hair follicles, sperm forming cells).forming cells).

Major Adverse Effects of Major Adverse Effects of chemotherapeutic drugschemotherapeutic drugs

Bone Marrow SuppressionBone Marrow SuppressionNeutropenia: Infection secondary to neutropenia is oneNeutropenia: Infection secondary to neutropenia is one

of the most serious complications of chemotherapy.of the most serious complications of chemotherapy.

• • Patients undergoing chemotherapy may be Patients undergoing chemotherapy may be immunocompromised.immunocompromised.

• • Special care should be taken to avoid exposure to contagions.Special care should be taken to avoid exposure to contagions.

• • Neutrophil counts need to be monitored.Neutrophil counts need to be monitored.

• • Without neutrophils, the usual signs of infection are masked. Without neutrophils, the usual signs of infection are masked. Fever may be the only indication of an infection.Fever may be the only indication of an infection.

Major Adverse Effects of chemotherapeutic Major Adverse Effects of chemotherapeutic drugsdrugs

Bone Marrow SuppressionBone Marrow SuppressionThrombocytopenia:Thrombocytopenia:

• • Bleeding from the nose and gums is common.Bleeding from the nose and gums is common.

• • Patients should avoid anticoagulants and aspirin.Patients should avoid anticoagulants and aspirin.

• • Care on performing procedure that cause bleeding or bruising.Care on performing procedure that cause bleeding or bruising.

Anemia:Anemia:

• • Primary cause of fatigue.Primary cause of fatigue.

• • Not as common as neutropenia or thrombocytopenia Not as common as neutropenia or thrombocytopenia (erythrocytes have a much longer life span).(erythrocytes have a much longer life span).

• • Treatment: Epoetin (erythropoietin, stimulates redTreatment: Epoetin (erythropoietin, stimulates red

blood cell production).blood cell production).


Injury to the GI/digestive tractInjury to the GI/digestive tract

Stomatitis: painful sores, increased incidence of infectionStomatitis: painful sores, increased incidence of infection

Diarrhea: loss of epithelial lining in the GI tract leadsDiarrhea: loss of epithelial lining in the GI tract leads

to impaired absorption of fluids and nutrientsto impaired absorption of fluids and nutrients

Nausea and Vomiting: Suppressed by premedication with Nausea and Vomiting: Suppressed by premedication with antiemetic drugs.antiemetic drugs.

• • Treatment with serotonin receptor antagonists Treatment with serotonin receptor antagonists

(block 5- HT3 receptors) e.g. Ondansetron (Zofran)(block 5- HT3 receptors) e.g. Ondansetron (Zofran)


Miscellaneous Adverse EffectsMiscellaneous Adverse Effects

Alopecia: reversible hair lossAlopecia: reversible hair loss

Reproductive toxicity: male sterility, birth defectsReproductive toxicity: male sterility, birth defects

Hyperuricemia: due to DNA breakdown– nephrotoxicityHyperuricemia: due to DNA breakdown– nephrotoxicity

Extravasation: local injury to tissues during IV Extravasation: local injury to tissues during IV administration (IV burn).administration (IV burn).

Carcinogenesis: Anticancer agents can be mutagenicCarcinogenesis: Anticancer agents can be mutagenic


Distinctive Toxicities of Some Distinctive Toxicities of Some Anticancer DrugsAnticancer Drugs

ToxicityToxicity Drug(s)Drug(s)

RenalRenal * methotrexate* methotrexate

HepaticHepatic cyclophosphamidecyclophosphamide

PulmonaryPulmonary BleomycinBleomycin

CardiacCardiac DoxorubicinDoxorubicin

ImmunosuppressiveImmunosuppressive Cyclophosphamide, Cyclophosphamide, methotrexatemethotrexate

OtherOther Cyclophosphamide Cyclophosphamide (hemorrhagic cystitis)(hemorrhagic cystitis)

*Less Bone marrow suppression – “marrow sparing”*Less Bone marrow suppression – “marrow sparing”

Prevention or Management of Prevention or Management of Drug Induced toxicitiesDrug Induced toxicities

The toxicities of some anticancer The toxicities of some anticancer drugs can be well anticipated and drugs can be well anticipated and hence be prevented by giving proper hence be prevented by giving proper medicationsmedications

E.g. mesna is given to prevent E.g. mesna is given to prevent hemorrhagic cystitis by hemorrhagic cystitis by cyclophosphamidecyclophosphamide

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ClassificatioClassification n

Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS) Agents

Antimetabolites (S phase) Alkylating agents

Capecitabine Altretamine

Cladribine Bendamustine

Clofarabine Busulfan

Cytarabine (ara-C) Carmustine

Fludarabine Chlorambucil

5-Fluorouracil (5-FU) Cyclophosphamide

Gemcitabine Dacarbazine

6-Mercaptopurine (6-MP) Lomustine

Methotrexate (MTX) Mechlorethamine

6-Thioguanine (6-TG) Melphalan

Temozolomide Epipodophyllotoxin (topoisomerase II inhibitor) (G1–S phase)

Thiotepa

Etoposide Anthracyclines

Taxanes (M phase) Daunorubicin

Albumin-bound paclitaxel Doxorubicin

Docetaxel Epirubicin

Paclitaxel Idarubicin

Vinca alkaloids (M phase) Mitoxantrone

Vinblastine Antitumor antibiotics

Vincristine Dactinomycin

Vinorelbine Mitomycin

Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I inhibitors)

Ixabepilone Irinotecan

Topotecan Antitumor antibiotics (G2–M phase) Platinum analogs

Bleomycin Carboplatin

Cisplatin

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Alkylating Agents- Alkylating Agents- hematologic and solid hematologic and solid tumorstumors

NitrosoureasNitrosoureas e.g. Carmustine (BCNU) - brain tumors e.g. Carmustine (BCNU) - brain tumors- Highly lipid soluble drugs.Highly lipid soluble drugs.

Mechlorethamine Mechlorethamine (Mustargen) (Mustargen) – Prodrug. – Prodrug. Hodgkin’s Hodgkin’s

disease. disease. - Highly irritant, care should be taken to avoid extravasation Highly irritant, care should be taken to avoid extravasation

during IV administration.during IV administration.

Both Drugs Both Drugs –– used topically to treat CTCL. used topically to treat CTCL. - monitor CBC and liver functions, systemic absorption can cause monitor CBC and liver functions, systemic absorption can cause

bone marrow suppression and hepatitis. bone marrow suppression and hepatitis. - Other side effects : allergic contact dermatitis, irritant Other side effects : allergic contact dermatitis, irritant

dermatitis, secondary cutaneous malignancies, and pigmentary dermatitis, secondary cutaneous malignancies, and pigmentary changes. changes.

- Carmustine can cause erythema and posttreatment Carmustine can cause erythema and posttreatment telangiectasiastelangiectasias

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Cyclophosphamide (Endoxan) Cyclophosphamide (Endoxan) It is a prodrug and is activated by the P-450 to It is a prodrug and is activated by the P-450 to

phosphoramide mustardphosphoramide mustard The active drug alkylates DNA, leading to abnormal The active drug alkylates DNA, leading to abnormal

base pairing and DNA strand breakagebase pairing and DNA strand breakage

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Uses Uses Cytotoxic and immunosuppressive agent.Cytotoxic and immunosuppressive agent.

Oral and IV in advanced CTLC.Oral and IV in advanced CTLC.

Other uses: pemphigus vulgaris, bullous pemphigoid, Other uses: pemphigus vulgaris, bullous pemphigoid,

cicatricial pemphigoid, paraneoplastic pemphigus, pyoderma cicatricial pemphigoid, paraneoplastic pemphigus, pyoderma gangrenosum, toxic epidermal necrolysis, Behcet's disease, gangrenosum, toxic epidermal necrolysis, Behcet's disease,

The oral dose is 2 to 3 mg/kg per day in divided doses, there The oral dose is 2 to 3 mg/kg per day in divided doses, there is a 4- to 6-week delay in onset of action.is a 4- to 6-week delay in onset of action.

IV pulse administration may produce lower cumulative dose IV pulse administration may produce lower cumulative dose

and a decreased risk of bladder cancerand a decreased risk of bladder cancer

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ADRADR Acrolein is the metaboliteAcrolein is the metabolite Responsible for causing hemorrhagic Responsible for causing hemorrhagic

cystitiscystitis– Suprapubic painSuprapubic pain– HematuriaHematuria– Cyctoscopic findings Cyctoscopic findings

This is prevented/treated by This is prevented/treated by MESNA (mercaptoethanesulfonate)MESNA (mercaptoethanesulfonate)

Rarely cyclophosphamide can cause Rarely cyclophosphamide can cause SIADH and pulmonary toxicitySIADH and pulmonary toxicity

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AntimetabolitesAntimetabolites

Folic Acid AnalogsFolic Acid Analogs Purine AnalogsPurine Analogs Pyrimidine AnalogsPyrimidine Analogs

MethotrexateMethotrexate AzathioprineAzathioprine FluorouracilFluorouracil

LegendDrug ClassSub-classPrototype Drug

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Methotrexate (MTX)Methotrexate (MTX) MTX is a folic acid analog that binds to DHFR, MTX is a folic acid analog that binds to DHFR,

interferes with the synthesis of THFinterferes with the synthesis of THF Antineoplastic, immunosuppressant and Antineoplastic, immunosuppressant and

antiinflammatoryantiinflammatory Used in RA, psoriasisUsed in RA, psoriasis Well absorbed orally; can also be given IM, IVWell absorbed orally; can also be given IM, IV It is bound to plasma proteins, It is bound to plasma proteins, does not cross the BBBdoes not cross the BBB

and most of the drug is excreted unchanged in urine.and most of the drug is excreted unchanged in urine. It is a weak acid, excreted better at high urine pH. It is a weak acid, excreted better at high urine pH.

Appropriate hydration and alkalinizing the urine is Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTXimportant to prevent renal tox with MTX

Should never be coadministered with trimethoprim-Should never be coadministered with trimethoprim-sulfamethoxazole, probenecid, salicylatessulfamethoxazole, probenecid, salicylates

Pregnancy and lactation are absolute contraindicationsPregnancy and lactation are absolute contraindications

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Contd..Contd.. Starting dose 5 - 7.5 mg/week. May be increased Starting dose 5 - 7.5 mg/week. May be increased

gradually to 20 to 30 mg/week if needed. 3 oral gradually to 20 to 30 mg/week if needed. 3 oral doses given at 12-hour intervals once weekly or doses given at 12-hour intervals once weekly or weekly IM.weekly IM.

Careful monitoring of liver function tests is Careful monitoring of liver function tests is necessary. necessary.

● Liver biopsy is recommended when the cumulative Liver biopsy is recommended when the cumulative dose reaches 1 to 1.5 g. dose reaches 1 to 1.5 g.

● A baseline liver biopsy for patients with increased A baseline liver biopsy for patients with increased potential risk for hepatic fibrosis, such as a history of potential risk for hepatic fibrosis, such as a history of alcohol abuse or infection with hepatitis B or C. alcohol abuse or infection with hepatitis B or C.

● Patients with significantly abnormal liver function Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug.hepatic fibrosis should not use this drug.

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ADRADR

Bone marrow suppression (BMS)Bone marrow suppression (BMS) MucositisMucositis Folic acid deficiency Folic acid deficiency The toxic effects of MTX on normal The toxic effects of MTX on normal

cells is reduced by administering cells is reduced by administering folinic acid (leucovorin)folinic acid (leucovorin)– This is called leucovorin rescue **** This is called leucovorin rescue **** – Higher the dose of MTX more the Higher the dose of MTX more the

leucovorin you give**leucovorin you give**

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Leucovorin RescueLeucovorin Rescue

Mechanism of action of Mechanism of action of methotrexate and the methotrexate and the effect of administration of effect of administration of leucovorin.leucovorin.

FH2 = dihydrofolateFH2 = dihydrofolate FH4 = tetrahydrofolateFH4 = tetrahydrofolate dTMP = deoxythymidine dTMP = deoxythymidine

monophosphatemonophosphate dUMP = deoxyuridine dUMP = deoxyuridine

mono phosphate. mono phosphate.

AzathioprineAzathioprine indicationsindications dermatomyositis, SLE, pemphigus dermatomyositis, SLE, pemphigus

vulgaris, Behcet’s diseasevulgaris, Behcet’s disease

Atopic dermatitis Atopic dermatitis Chronic actinic dermatitisChronic actinic dermatitisPyoderma gangrenosumPyoderma gangrenosumPityriasis rubra pilarisPityriasis rubra pilarisCutaneous vasculitisCutaneous vasculitisPsoriasisPsoriasisLichen planusLichen planusphotodermatosisphotodermatosis

AzathioprineAzathioprine Prodrug, absorbed from the gut.Prodrug, absorbed from the gut. Does not cross the BBB but crosses the palcentaDoes not cross the BBB but crosses the palcenta Starting dose is 1 - 2 mg/kg/day. Therapeutic effect after Starting dose is 1 - 2 mg/kg/day. Therapeutic effect after

6 - 8 wks6 - 8 wks

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5-FU causes, “thymidineless 5-FU causes, “thymidineless death” of cellsdeath” of cells

UsesUses Topical formulations are used in Topical formulations are used in

multiple actinic keratoses, multiple actinic keratoses, Bowen's disease, and superficial Bowen's disease, and superficial basal cell carcinomas not basal cell carcinomas not amenable to other treatments.amenable to other treatments.

Applied twice daily for 2 to 4 Applied twice daily for 2 to 4 weeksweeks

Treated areas may become Treated areas may become severely inflamed but subsides severely inflamed but subsides after the drug is stopped. after the drug is stopped.

Intralesional injection of 5-FU in Intralesional injection of 5-FU in keratoacanthomas, wartskeratoacanthomas, warts

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Vinka alkaloids (Vinblastine)Vinka alkaloids (Vinblastine)

Act primarily on the M Act primarily on the M phase of cancer cell phase of cancer cell cyclecycle

Used in Kaposi's Used in Kaposi's sarcoma (intralesional) sarcoma (intralesional) and advanced CTCL.and advanced CTCL.

Toxicity:Toxicity:Bone marrow suppressionBone marrow suppressionAnorexia, nausea, Anorexia, nausea,

vomiting, diarrheavomiting, diarrheaAlopeciaAlopecia

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Cc1 cancer derma